Acyl derivatives of azolones

ABSTRACT

The invention is concerned with the compounds having the formula ##STR1## the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Y is CH or N; R 1 , R 2  and R 3  each independently are hydrogen or C 1-4  alkyl; R 4  and R 5  each independently are hydrogen, halo, C 1-4  alkyl, C 1-4  alkyloxy, hydroxy, trifiuoromethyl, trifiuoromethyloxy or difluoromethyloxy; R 6  is hydrogen; or R 6  is phenyl optionally substituted with halo; pyridinyl; furanyl; thienyl; 3-chloro-benzo[b]thien-2-yl; trifiuoromethyl; C 1-4  alkyloxycarbonyl; dihalophenylcyclopropanyl; C 3-6  cycloalkyl; adamantyl; C 2-6  alkenyl optionally substituted with halophenyl; or C 1-4  alkyl optionally substituted with halo, phenyl, halophenyl, dihalophenyl, phenyloxy, piperidinyl, pyrrolidinyl, piperazinyl, C 1-4  alkylpiperazinyl, C 1-4  alkylcarbonylpiperazinyl, C 1-4  alkyloxycarbonylpiperazinyl, phthalimino, amino, mono- or di(C 1-20 )alkylamino or C 3-6  cycloalkylamino; Z is C═O or CHOH; and ##STR2## is a radical of formula ##STR3## Compositions comprising said compounds, processes for preparing the same and the use of these compounds as a medicine.

The present invention is concerned with substituted azolone derivativeswhich are potent anti-Helicobacter agents.

U.S. Pat. No. 4,791,111 discloses azolones having a structure similar tothat of the present compounds and which are intermediates in thepreparation of[[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazolesand -1H-1,2,4-triazoles.

In U.S. Pat. No. 4,931,444 are described substituted azolone derivativeshaving 5-lipoxygenase inhibiting activity. The present compounds aredistinguished therefrom by their useful anti-Helicobacter activity.

In the eradication of Helicobacter, dual therapies comprising theseparate administration of two antibiotic drugs have not beensatisfactory because of one or more of the following reasons: a loweradication rate, numerous side effects and development of resistance byHelicobacter. Triple therapies comprising the administration of twoantibiotics and a bismuth compound have been shown to be effective, butare very demanding for the patients and are also compromised by sideeffects. The present compounds show the advantage that they may be usedin a monotherapy in the eradication of Helicobacter pylori and relatedspecies.

The present invention is concerned with compounds having the formula##STR4## the pharmaceutically acceptable addition salts and thestereochemically isomeric forms thereof, wherein

Y is CH or N;

R¹, R² and R³ each independently are hydrogen or C₁₋₄ alkyl;

R⁴ and R⁵ each independently are hydrogen, halo, C₁₋₄ alkyl, C₁₋₄alkyloxy, hydroxy, trifluoromethyl, trifluoromethyloxy ordifluoromethyloxy;

R⁶ is hydrogen; or

R⁶ is phenyl optionally substituted with halo; pyridinyl; furanyl;thienyl; 3-chlorobenzo[b]thien-2-yl; trifluoromethyl; C₁₋₄alkyloxycarbonyl; dihalophenylcyclopropanyl;

C₃₋₆ cycloalkyl; adamantyl; C₂₋₆ alkenyl optionally substituted withhalophenyl; or C₁₋₄ alkyl optionally substituted with halo, phenyl,halophenyl, dihalophenyl, phenyloxy, piperidinyl, pyrrolidinyl,piperazinyl, C₁₋₄ alkylpiperazinyl, C₁₋₄ alkylcarbonylpiperazinyl, C₁₋₄alkyloxycarbonylpiperazinyl, phthalimino, amino, mono- ordi(C₁₋₂₀)alkylamino or C₃₋₆ cycloalkylamino;

Z is C═O or CHOH; and ##STR5## is a radical of formula ##STR6##

As used in the foregoing definitions halo defines fluoro, chloro, bromoand iodo; C₁₋₄ alkyl defines straight and branched chain saturatedhydrocarbon radicals having from 1 to 4 carbon atoms such as, forexample, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl and 1,1-dimethylethyl; C₁₋₆ alkyl defines C₁₋₄ alkylradicals as defined hereinbefore and the higher homologs thereof havingfrom 5 to 6 carbon atoms such as, for example, pentyl and hexyl; C₁₋₂₀alkyl defines C₁₋₄ alkyl radicals as defined hereinbefore and the higherhomologs thereof having from 5 to 20 carbon atoms; C₃₋₆ cycloalkyl isgeneric to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C₂₋₆alkenyl defines straight and branch chained hydrocarbon radicalscontaining one or two double bonds and having from 2 to 6 carbon atoms.

The term pharmaceutically acceptable addition salt as used hereinbeforedefines the non-toxic, therapeutically active addition salt forms whichthe compounds of formula (I) may form. The compounds of formula (Dhaving basic properties may be converted into the correspondingtherapeutically active, non-toxic acid addition salt forms by treatingthe free base form with a suitable amount of an appropriate acidfollowing conventional procedures. Appropriate acids comprise, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and thelike acids. The term addition salt as used hereinabove also comprisesthe solvates which the compounds of formula (I) as well as the saltsthereof, are able to form. Such solvates are for example hydrates,alcoholates and the like.

The term stereochemically isomeric forms as used hereinbefore definesthe different isomeric as well as conformational forms which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereochemically and conformationally isomeric forms, saidmixtures containing all diastereomers, enantiomers and/or conformers ofthe basic molecular structure. All stereochemically isomeric forms ofthe compounds of formula (I) both in pure form or in admixture with eachother are intended to be embraced within the scope of the presentinvention.

The absolute configuration of each chiral center may be indicated by thestereochemical descriptors R and S. For the compounds having two chiralcenters, the relative stereodescriptors R* and S* are used in accordancewith the Chemical Abstracts rules (Chemical Substance Name SelectionManual (CA), 1982 Edition, Vol. III, Chapter 20).

Some compounds of the present invention may exist in differenttautomeric forms and all such tautomeric forms are intended to beincluded within the scope of the present invention.

A first group of interesting compounds are those compounds of formula(I) wherein R⁴ is halo and R⁵ is hydrogen.

A second group of interesting compounds are those compounds of formula(I) wherein ##STR7## is a radical of formula (a-1) or (a-2).

A third group of interesting compounds are those compounds of formula(I) wherein Y is N and R¹ is hydrogen.

A fourth group of interesting compounds are those compounds of formula(I) wherein R² is C₁₋₄ alkyl and R³ is hydrogen.

A fifth group of interesting compounds are those compounds of formula(I) wherein R⁶ is pyridinyl, phenyl, halophenyl, benzyl, C₃₋₆cycloalkyl, C₁₋₄ alkyloxycarbonyl, methyl or trifluoromethyl.

Preferred compounds are those compounds of formula (I) wherein

R¹, R³ and R⁵ are hydrogen;

R² is C₁₋₄ alkyl;

R⁴ is halo; and

Y is N.

More preferred compounds are those compounds of formula (I) wherein

R¹, R³ and R⁵ are hydrogen;

R² is ethyl;

R⁴ is halo;

Y is N;

R⁶ is pyridinyl, phenyl, halophenyl, benzyl, C₃₋₆ cycloalkyl, C₁₋₄alkyloxycarbonyl, methyl or trifluoromethyl; and ##STR8## is a radicalof formula (a-1) or (a-2).

The most preferred compounds are

1-[4-[2-[1-(4-chlorobenzoyl)propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]phenyl]-4-(cyclopropylcarbonyl)piperazine;

1-(4-chlorobenzoyl)-4-[5-[2-[1-(4-chlorobenzoyl)propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]-2-pyridinyl]piperazine;

1-benzoyl-4-[4-[2-[1-[(4-chlorophenyl)hydroxymethyl]propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]phenyl]piperazine;

1-(4-chlorobenzoyl)-4-[4-[2-[1-[(4-chlorophenyl)hydroxymethyl]propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]phenyl]piperazine;

the pharmaceutically acceptable addition salts and the stereochemicallyisomeric forms thereof.

Analogous procedures for the preparation of compounds such as thepresent compounds of formula (I) have been described in U.S. Pat. No.4,791,111 and U.S. Pat. No. 4,931,444.

The compounds of formula (I) may be prepared by N-acylating anintermediate of formula (II) with a reagent of formula (III) wherein Lis a reactive leaving group such as, for example, a halogen, di(C₁₋₄alkyl)amino or the like. ##STR9##

The above N-acylation may conveniently be conducted in an appropriatesolvent in the presence of a suitable base. Appropriate solvents are,for example dipolar aprotic solvents, e.g. N,N-dimethylformamide,N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone; aromaticsolvents, e.g. benzene, methylbenzene; an ether, e.g. 1,1'-oxybisethane,tetrahydrofuran, 1-methoxy-2-propanol; a halogenated hydrocarbon, e.g.dichloromethane, trichloromethane; or a mixture of such solvents.Suitable bases are, for example, sodium bis(trimethylsilyl)amide, sodiumhydroxide, alkali metal and earth alkaline metal carbonates or hydrogencarbonates, e.g. sodium or potassium carbonate; or organic bases, e.g.triethylamine, pyridine and the like bases.

The compounds of formula (I) wherein R⁶ is methyl or trifluoromethyl,said R⁶ being represented by R^(6-a) and said compounds by the formula(I-a), can be prepared by reacting an intermediate of formula (II) withacetic anhydride (III-a) or trifluoroacetic anhydride (III-b), in areaction-inert solvent, e.g. dichloromethane, toluene and the like,optionally in the presence of a base, e.g. alkali metal and earthalkaline metal carbonates or hydrogen carbonates, e.g. sodium orpotassium carbonate. ##STR10##

The compounds of formula (I) can also be prepared by N-alkylating anintermediate of formula (VI) with a reagent of formula (VII) in anappropriate solvent and in the presence of a suitable base. ##STR11##

The compounds of formula (I) can also be converted into each otherfollowing art-known procedures of functional group transformation.

For example, the compounds of formula (I) wherein R⁶ is C₁₋₄ alkylsubstituted with piperidinyl, pyrrolidinyl, piperazinyl, C₁₋₄alkylpiperazinyl, C₁₋₄ alkylcarbonylpiperazinyl, C₁₋₄alkyloxycarbonylpiperazinyl, amino, mono- or di(C₁₋₂₀)alkylamino or C₃₋₆cycloalkylamino, said substituents being represented by R⁷ and saidcompounds by the formula (I-b), may be prepared by the reaction of acompound of formula (I-c) with a reagent of formula (IV) in areaction-inert solvent, e.g. N,N-dimethylformamide. ##STR12##

Further, the compounds of formula (I) wherein Z represents C═O can beconverted into the compounds of formula (I) wherein Z represents CHOHfollowing art-known reductions. For example, said reduction canconveniently be conducted by reaction with a metal hydride or complexmetal hydride, e.g. sodium borohydride, sodium cyanoborohydride and thelike in water, 1-methyl-pyrrolidinone, acetonitrile, an alcoholicmedium, e.g. methanol, ethanol, or an ether, e.g. tetrahydrofuran,1,4-dioxane; or in a mixture of such solvents.

Alternatively, said reduction can be conducted by reaction withtris(1-methylethoxy)potassium hydroborate, tris(1-methylpropyl)sodiumhydroborate or tris(1-methylpropyl)potassium hydroborate in areaction-inert solvent, e.g. tetrahydrofuran or N,N-dimethylformamide.

Optionally, the reaction of the compound of formula (I-c) with a reagentof formula (IV) and the reduction described above may be conducted in asingle reaction vessel.

Finally, pure isomeric forms of the compounds of formula (D can beseparated from the mixture by conventional separation methods. Inparticular, the enantiomers may be separated by column chromatographyusing a chiral stationary phase such as a suitably derivatizedcellulose, for example, tri(dimethylcarbamoyl)cellulose (Chiralcel OD®)and similar chiral stationary phases.

In all foregoing and in the following preparations, the reactionproducts may be isolated from the reaction mixture and, if necessary,further purified according to methodologies generally known in the art.

The intermediates of formula (II) may be prepared by the reaction of acompound of formula (V) with an acid, e.g. hydrobromic acid and thelike. ##STR13##

The intermediates of formula (VI) may be prepared following theprocedures as described hereinabove for the preparation of the compoundsof formula (I) from the intermediates of formula (II).

The compounds of formula (I), the pharmaceutically acceptable additionsalts and the stereochemically isomeric forms thereof display usefulpharmacological activity against Helicobacter species; e.g. Helicobacterpylori, Helicobacter mustelae, Helicobacter felis and the like, inparticular Helicobacter pylori.

Particularly important in this context is the finding that the subjectcompounds show inhibitory activity against the growth of Helicobacter aswell as bactericidal activity against said bacteria. The bactericidaleffect on Helicobacter was determined with suspension cultures by meansof a procedure described in Antimicrob. Agents Chemother., 1991, vol.35, pp. 869-872.

An interesting feature of the present compounds relates to their highlyspecific activity against Helicobacter. The compounds of formula (I)were found to show no inhibitory activity against any of the followingspecies: Campylobactor jejuni, Campylobacter coli, Campylobacter fetus,Campylobacter sputorum, Vibrio spp., Staphylococcus aureus andEscherichia coil, tested at concentrations up to 10⁻⁵ M.

An important asset of the present compounds is their sustained activityagainst H. pylori at pH below the neutral pH. Activity at a low pH invitro may indicate that a compound is not adversely affected by theacidic environment of the stomach in vivo.

Consequently, the subject compounds are considered to be valuabletherapeutical drugs for treating warm-blooded animals, particularlyhumans, suffering from Helicobacter related diseases or afflictions.Examples of said diseases or afflictions are gastritis, stomach ulcers,duodenal ulcers and gastric cancer.

In view of their useful anti-Helicobacter properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes. To prepare the pharmaceutical compositions ofthis invention, an effective amount of the particular compound, in baseor addition salt form, as the active ingredient is combined in intimateadmixture with a pharmaceutically acceptable carrier, which may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, or by parenteral injection. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcoholsand the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions: or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed.

When the pharmaceutical composition takes the form of an aqueoussolution, those compounds of formula (I) which display low solubilitymay be formulated as a salt form, or a co-solvent may be added which iswater-miscible and physiologically acceptable, e.g. dimethylsulfoxideand the like, or the compounds of formula (I) may be solubilized with asuitable carrier, e.g. a cyclodextrin (CD) or in particular acyclodextrin derivative such as the cyclodextrin derivates described inU.S. Pat. No. 3,459,731, EP-A-149,197 (Jul. 24, 1985), EP-A-197,571(Oct. 15, 1986), U.S. Pat. No. 4,535,152 or WO 90/12035 (Oct. 18, 1990).Appropriate cyclodextrin derivatives are α-, β-, γ-cyclodextrins orethers and mixed ethers thereof wherein one or more of the hydroxygroups of the anhydroglucose units of the cyclodextrin are substitutedwith C₁₋₆ alkyl, particularly methyl, ethyl or isopropyl; hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl;carboxyC₁₋₆ alkyl, particularly carboxymethyl or carboxyethyl; C₁₋₆alkyl-carbonyl, particularly acetyl; C₁₋₆ alkyloxycarbonylC₁₋₆ alkyl orcarboxyC₁₋₆ alkyl-oxyC₁₋₆ alkyl, particularly carboxymethoxypropyl orcarboxyethoxypropyl; C₁₋₆ alkylcarbonyloxyC₁₋₆ alkyl, particularly2-acetyloxypropyl. Especially noteworthy as complexants and/orsolubilizers are β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD.

The term mixed ether denotes cyclodextrin derivatives wherein at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxypropyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of theaverage number of moles of alkoxy units per mole of anhydroglucose. TheM.S. value can be determined by various analytical techniques such asnuclear magnetic resonance (NMR), mass spectrometry (MS) and infraredspectroscopy (IR). Depending on the technique used, slightly differentvalues may be obtained for one given cyclodextrin derivative. In thecyclodextrin hydroxyalkyl derivatives for use in the compositionsaccording to the present invention the M.S. as determined by massspectrometry is in the range of 0.125 to 10, in particular of 0.3 to 3,or from 0.3 to 1.5. Preferably the M.S. ranges from about 0.3 to about0.8, in particular from about 0.35 to about 0.5 and most particularly isabout 0.4. M.S. values determined by NMR or IR preferably range from 0.3to 1, in particular from 0.55 to 0.75.

The average substitution degree (D.S.) refers to the average number ofsubstituted hydroxyls per anhydroglucose unit. The D.S. value can bedetermined by various analytical techniques such as nuclear magneticresonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR).Depending on the technique used, slightly different values may beobtained for one given cyclodextrin derivative. In the cyclodextrinderivatives for use in the compositions according to the presentinvention the D.S. as determined by MS is in the range of 0.125 to 3, inparticular of 0.2 to 2 or from 0.2 to 1.5. Preferably the D.S. rangesfrom about 0.2 to about 0.7, in particular from about 0.35 to about 0.5and most particularly is about 0.4. D.S. values determined by NMR or IRpreferably range from 0.3 to 1, in particular from 0.55 to 0.75. Moreparticular β- and γ-cyclodextrin hydroxyalkyl derivatives for use in thecompositions according to the present invention are partiallysubstituted cyclodextrin derivatives wherein the average degree ofalkylation at hydroxyl groups of different positions of theanhydroglucose units is about 0% to 20% for the 3 position, 2% to 70%for the 2 position and about 5% to 90% for the 6 position. Preferablythe amount of unsubstituted β- or γ-cyclodextrin is less than 5% of thetotal cyclodextrin content and in particular is less than 1.5%. Anotherparticularly interesting cyclodextrin derivative is randomly methylatedβ-cyclodextrin.

Most preferred cyclodextrin derivatives for use in the present inventionare those partially substituted β-cyclodextrin ethers or mixed ethershaving hydroxypropyl, hydroxyethyl and in particular 2-hydroxypropyland/or 2-(1-hydroxypropyl) substituents.

The most preferred cyclodextrin derivative for use in the compositionsof the present invention is hydroxypropyl-β-cyclodextrin having a M.S.in the range of from 0.35 to 0.50 and containing less than 1.5%unsubstituted β-cyclodextrin. M.S. values determined by NMR or IRpreferably range from 0.55 to 0.75.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions and the like, and segregatedmultiples thereof.

In view of the usefulness of the subject compounds in the treatment ofHelicobacter related diseases it is evident that the present inventionprovides a method of treating warm-blooded animals, in particularhumans, suffering from Helicobacter related diseases, said methodcomprising the systemic administration of a pharmaceutically effectiveamount of a compound of formula (I), a pharmaceutically acceptableaddition salt thereof or a stereochemically isomeric form thereof, inadmixture with a pharmaceutical carrier. In a further aspect of theinvention, the subjects compounds are administered for use as amedicine.

In general it is contemplated that an effective daily amount would befrom 0.05 mg/kg to 50 mg/kg body weight, preferably from 0.1 mg/kg to 30mg/kg body weight and more preferably form 0.5 mg/kg to 10 mg/kg bodyweight.

It is evident that said effective daily amount may be lowered orincreased depending on the response of the treated subject and/ordepending on the evaluation of the physician prescribing the compoundsof the instant invention. The effective ranges mentioned hereinabove aretherefore guidelines only and are not intended to limit the scope or useof the invention to any extent.

Optionally, other active compounds used for the eradication ofHelicobacter can be administered in combination with the compounds ofthe present invention. The administration may occur separately (i.e.simultaneously, concurrently or consecutively) or the different drugsmay be combined in one dosage form. Suitable compounds for a combinationtherapy are bismuth compounds, e.g. bismuth subeitrate, bismuthsubsalicylate, and the like, antibiotics, e.g. ampicillin, amoxicillin,clarithromycin and the like, H₂ -receptor antagonists, e.g. cimetidine,ranitidine and the like, and in particular, proton pump inhibitors, e.g.omeprazole, lansoprazole, pantoprazole and the like. For the compoundscited to be useful for a combination therapy with the compounds offormula (I) an effective daily amount would be from 0.05 mg/kg to 50mg/kg body weight.

EXIPERIMENTAL PART

Hereinafter, "DMF" means N,N-dimethylformamide, "DMSO" means dimethylsulfoxide and "TIFF" means tetrahydrofuran.

EXAMPLE 1

a) A mixture of (±)-ethyl4-[4-[2-[1-(4-chlorobenzoyl)propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinecarboxylate(15 g) in a hydrobromic acid solution 48% in water (150 ml) was stirredand refluxed or 6 hours and then stirred overnight. The mixture wasevaporated, the residue was dissolved in CH₂ Cl₂ and washed with NaHCO₃/H₂ O. The organic layer was dried, filtered and the solvent evaporate&.The residue was dissolved in 2-propanol and crystallized into thehydrochloric acid salt (1:2) in 2-propanol. The precipitate was filteredoff and recrystallized from CH₃ CN, yielding 7.9 g (2.2%) of(±)-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[4-(1-piperazinyl)phenyl]-3H-1,2,4-triazol-3-one. dihydrochloride . monohydrate; mp. 175.9° C. (interm. 1).

b) Sodium hydroxide (4 g) dissolved in water (20 ml) was added to amixture of intermediate (1) (6 g) in CH₂ Cl₂ (180 ml) and the mixturewas stirred for 30 minutes. Benzeneacetyl chloride (2.3 g) in CH₂ Cl₂(20 ml) was added dropwise and the mixture was stirred at 20° C. for 2hours. Water was added and the layers were separated, The organic layerwas dried, filtered and the solvent evaporated. The residue wascrystallized from 2-propanol. The precipitate was filtered off anddried, yielding 4.7 g (59%) of(±)-1-[4-[2-[1-(4-chlorobenzoyl)propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]phenyl]-4-(phenylacetyl)piperazine;mp. 172° C. (comp. 1).

EXAMPLE 2

A mixture of acetic anhydride (10.2 g), intermediate (1) (10 g) andsodium carbonate (10.6 g) in toluene (200 ml) was stirred and refluxedovernight. The mixture was cooled, water was added and the layers wereseparated. The organic layer was dried, filtered and the solventevaporated. The residue was crystallized from 2-propanol and dried,yielding 8 g (89%) of(±)-1-acetyl-4-[4-[2-[1-(4-chlorobenzoyl)propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]phenyl]piperazine;mp. 125° C. (comp. 2).

EXAMPLE 3

A mixture of compound (27) (2 g) in DMF (100 ml) was stirred at -40° C.K[OCH(CH₃)₂ ]₃ BH 1M in THF (11 ml) was added dropwise and the mixturewas stirred overnight. The mixture was poured into water and stirred for2 hours. The precipitate was filtered off and purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 98/2). The purefractions were collected and evaporated. The residue was triturated inethylacetate/diisopropyl ether, yielding 1 g (51%) of(±)-(R*,R*)-1-[5-[2-[1-[(4-chlorophenyl)hydroxymethyl]propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]-2-pyridinyl]-4-(2-pyridinylcarbonyl)piperazine;mp. 210° C. (comp. 3).

EXAMPLE 4

A mixture of compound (16) (0.35 g) in 1-propanamine (0.5 ml) and DMF (2ml) was stirred at room temperature overnight. The mixture was purifiedby HPLC over silica gel (eluent: CH₂ Cl₂ 100 to CH₂ Cl₂ /CH₃ OH 90/10over a 20 minute period and 120 ml/minute and to CH₃ OH 100 after 20minutes). The desired fraction was collected and evaporated, yielding asolution of 0.22 g(±)-4-[5-[2-[1-(4-chlorobenzoyl)propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]-2-pyridinyl]-1-[(propylamino)acetyl]-piperazinein DMSO (21 ml) (60.6%) (comp. 4).

EXAMPLE 5

A mixture of compound (16) (0.25 g) in 1-propanamine (0.25 ml) and DMF(1.5 ml) was stirred for 1 hour. K[OCH(CH₃)₂ ]₃ BH 1M in THF (1.5 ml)was added and the mixture was stirred for 1 hour. A NH₄ Cl solution(0.25 ml) was added, the mixture was stirred for 1 hour and thenpurified by HPLC over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 90/10 to CH₂Cl₂ /CH₃ OH 70/30 over a 20 minutes period and 120 ml/minute). Thedesired fraction was collected and evaporated, yielding a solution of0.09 g(±)-(R*,R*)-4-[5-[2-[1-[(4-chlorophenyl)hydroxymethyl]propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]-2-pyridinyl]-1-[(propylamino)acetyl]piperazinein DMSO (8.5 ml) (32.2%) (comp. 5).

The compounds listed in the table hereinbelow were prepared inaccordance with one of the above described procedures.

    __________________________________________________________________________     ##STR14##                                                                    Co.                                                                              Ex.                                                                        no.                                                                              no.                                                                              R.sup.6         A  Z     Physical data                                  __________________________________________________________________________     1 1  C.sub.6 H.sub.5CH.sub.2                                                                       CH CO    mp. 172° C.                              6 1  2,4-ClC.sub.6 H.sub.3CH.sub.2                                                                 CH CO    --                                              7 1  cC.sub.3 H.sub.5                                                                              CH CO    --                                              8 1  cC.sub.6 H.sub.11                                                                             CH CO    --                                              9 1  4-ClC.sub.6 H.sub.4                                                                           CH CO    --                                             10 1                                                                                 ##STR15##      CH CO    --                                             11 1  CH.sub.3CH.sub.2OCO                                                                           CH CO    --                                             12 1  ClCH.sub.2      CH CO    mp. 176° C.                             13 1  C.sub.6 H.sub.5 CH CO    mp. 180° C./HCl                         14 1  4-ClC.sub.6 H.sub.4                                                                           N  CO    --                                             15 1  C.sub.6 H.sub.5CH.sub.2                                                                       N  CO    mp. 166° C.                             16 1  ClCH.sub.2      N  CO    --                                             17 1  3-pyridinyl     N  CO    mp. 159° C.                             18 1  2-thienyl       CH CO    --                                             19 1  C.sub.6 H.sub.5OCH.sub.2                                                                      CH CO    --                                             20 1  2-furanyl       CH CO    --                                             21 1  3-chloro-2-benzo[b]thienyl                                                                    CH CO    --                                             22 1                                                                                 ##STR16##      CH CO    --                                             23 1  CH.sub.3CHCHCHCH                                                                              CH CO    --                                             24 1                                                                                 ##STR17##      CH CO    --                                             25 1  4-ClC.sub.6 H.sub.4CHCH                                                                       CH CO    --                                             26 1  3-pyridinyl     CH CO    mp. 202° C./2HCl                        27 1  2-pyridinyl     N  CO    mp. 180° C.                              2 2  CH.sub.3        CH CO    mp. 125° C.                             28 2  CF.sub.3        CH CO    --                                             29 2  CH.sub.3        N  CO    mp. 178° C.                              3 3  2-pyridinyl     N  CHOH  mp. 210° C./(R*, R*)                    30 3  CH.sub.3        CH CHOH  mp. 223° C./(R*, R*)                    31 3                                                                                 ##STR18##      CH CHOH  mp. 207° C./(R*, R*)                    32 3  CH.sub.3        N  CHOH  mp. 252° C./(R*, R*)                    33 3  C.sub.6 H.sub.5CH.sub.2                                                                       N  CHOH  mp. 204° C./(R*, R*)                    34 3                                                                                 ##STR19##      N  CHOH  mp. 195° C./(R*, R*)                    35 3  4-ClC.sub.6 H.sub.4                                                                           CH CHOH  mp. 218° C./(R*, R*)                    36 3  C.sub.6 H.sub.4 CH CHOH  mp. 197° C./(R*, R*)                    37 3  3-pyridinyl     N  CHOH  mp. 224° C./(R*, R*)                    38 3  1-piperidinylmethyl                                                                           N  CHOH  mp. 192° C./(R*, R*)                    39 3                                                                                 ##STR20##      CH CHOH  mp. 192° C./(R*, R*)                    40 3  4-ClC.sub.6 H.sub.4                                                                           N  CHOH  mp. 197° C./(R*, R*)                    41 3  1-piperidinylmethyl                                                                           CH CHOH  mp. 208° C./(R*, R*)                    4  4  CH.sub.3(CH.sub.2).sub.2NHCH.sub.2                                                            N  CO    --                                             42 4  (CH.sub.3).sub.2CHNHCH.sub.2                                                                  N  CO    --                                             43 4  CH.sub.3(CH.sub.2).sub.3NHCH.sub.2                                                            N  CO    --                                             44 4  C.sub.2 H.sub.5CH(CH.sub.3)NHCH.sub.2                                                         N  CO    --                                             100                                                                              4  CH.sub.3(CH.sub.2).sub.4NHCH.sub.2                                                            N  CO    --                                             45 4  cC.sub.5 H.sub.9NHCH.sub.2                                                                    N  CO    --                                             46 4  cC.sub.6 H.sub.11 NHCH.sub.2                                                                  N  CO    --                                             47 4  (C.sub.2 H.sub.5).sub.2NCH.sub.2                                                              N  CO    --                                             48 4  (C.sub.3 H.sub.7).sub.2NCH.sub.2                                                              N  CO    --                                             49 4  1-pyrrolidinylmethyl                                                                          N  CO    --                                             50 4                                                                                 ##STR21##      N  CO    --                                             51 4  (C.sub.4 H.sub.9).sub.2NCH.sub.2                                                              N  CO    --                                             52 4  (C.sub.5 H.sub.11).sub.2NCH.sub.2                                                             N  CO    --                                             53 4  CH.sub.3(CH.sub.2).sub.2NHCH.sub.2                                                            CH CO    --                                             54 4  (CH.sub.3).sub.2CHNHCH.sub.2                                                                  CH CO    --                                             55 4  CH.sub.3(CH.sub.2).sub.3NHCH.sub.2                                                            CH CO    --                                             56 4  C.sub.2 H.sub.5CH(CH.sub.3)NHCH.sub.2                                                         CH CO    --                                             57 4  CH.sub.3(CH.sub.2).sub.4NHCH.sub.2                                                            CH CO    --                                             58 4  cC.sub.5 H.sub.9NHCH.sub.2                                                                    CH CO    --                                             59 4  cC.sub.6 H.sub.11NHCH.sub.2                                                                   CH CO    --                                             60 4  (C.sub.2 H.sub.5).sub.2NCH.sub.2                                                              CH CO    --                                             61 4  (C.sub.3 H.sub.7).sub.2NCH.sub.2                                                              CH CO    --                                             62 4  (C.sub.4 H.sub.9).sub.2NCH.sub.2                                                              CH CO    --                                             63 4  (C.sub.5 H.sub.11).sub.2NCH.sub.2                                                             CH CO    --                                             64 4  1-pyrrolidinylmethyl                                                                          CH CO    --                                             65 4                                                                                 ##STR22##      CH CO    --                                             66 4  1-piperidinylmethyl                                                                           CH CO    mp. 165° C.                             67 4                                                                                 ##STR23##      CH CO    mp. 210° C./2HCl                        68 4                                                                                 ##STR24##      N  CO    mp. 168° C.                             69 4  (CH.sub.3).sub.2NCH.sub.2                                                                     N  CO    mp. 174.0° C.                           70 4  1-piperidinylmethyl                                                                           N  CO    mp. 200° C.                             71 4                                                                                 ##STR25##      CH CO    mp. 226° C./2HCl                        72 4                                                                                 ##STR26##      N  CO    mp. 153° C.                             73 4  (C.sub.7 H.sub.15).sub.2NCH.sub.2                                                             CH CO    --                                             74 4  (C.sub.12 H.sub.25).sub.2NCH.sub.2                                                            CH CO    --                                             75 4  (C.sub.14 H.sub.29).sub.2NCH.sub.2                                                            CH CO    --                                              5 5  CH.sub.3(CH.sub.2).sub.2NHCH.sub.2                                                            N  CHOH  (R*, R*)                                       76 5  (CH.sub.3).sub.2CHNHCH.sub.2                                                                  N  CHOH  (R*, R*)                                       77 5  CH.sub.3(CH.sub.2).sub.3NHCH.sub.2                                                            N  CHOH  (R*, R*)                                       78 5                                                                                 ##STR27##      CH CHOH  (R*, R*)                                       79 5  1-pyrrolidinylmethyl                                                                          CH CHOH  (R*, R*)                                       80 5  (C.sub.3 H.sub.7).sub.2NCH.sub.2                                                              CH CHOH  (R*, R*)                                       81 5  (C.sub.4 H.sub.9).sub.2NCH.sub.2                                                              CH CHOH  (R*, R*)                                       82 5  (C.sub.2 H.sub.5).sub.2NCH.sub.2                                                              CH CHOH  (R*, R*)                                       83 5  cC.sub.6 H.sub.11NHCH.sub.2                                                                   CH CHOH  (R*, R*)                                       84 5  cC.sub.5 H.sub.9NHCH.sub.2                                                                    CH CHOH  (R*, R*)                                       85 5  CH.sub.3(CH.sub.2).sub.4NHCH.sub.2                                                            CH CHOH  (R*, R*)                                       86 5  C.sub.2 H.sub.5CH(CH.sub.3)NHCH.sub.2                                                         CH CHOH  (R*, R*)                                       87 5  CH.sub.3(CH.sub.2).sub.3NHCH.sub.2                                                            CH CHOH  (R*, R*)                                       88 5  (CH.sub.3).sub.2NHCH.sub.2                                                                    CH CHOH  (R*, R*)                                       89 5  CH.sub.3(CH.sub.2).sub.2NHCH.sub.2                                                            CH CHOH  (R*, R*)                                       90 5                                                                                 ##STR28##      N  CHOH  (R*, R*)                                       91 5  1-pyrrolidinylmethyl                                                                          N  CHOH  (R*, R*)                                       92 5  C.sub.2 H.sub.5CH(CH.sub.3)NHCH.sub.2                                                         N  CHOH  (R*, R*)                                       93 5  CH.sub.3(CH.sub.2).sub.4NHCH.sub.2                                                            N  CHOH  (R*, R*)                                       94 5  cC.sub.5 H.sub.9NHCH.sub.2                                                                    N  CHOH  (R*, R*)                                       95 5  cC.sub.6 H.sub.11NHCH.sub.2                                                                   N  CHOH  (R*, R*)                                       96 5  (C.sub.2 H.sub.5).sub.2NCH.sub.2                                                              N  CHOH  (R*, R*)                                       97 5  (C.sub.3 H.sub.7).sub.2NCH.sub.2                                                              N  CHOH  (R*, R*)                                       98 5  (C.sub.4 H.sub.9).sub.2NCH.sub.2                                                              N  CHOH  (R*, R*)                                       99 5  (C.sub.5 H.sub.11).sub.2NCH.sub.2                                                             N  CHOH  (R*, R*)                                       101                                                                              1  H               N  CO    183.1° C.                               102                                                                              1  CH.sub.3(CH.sub.2).sub.2                                                                      N  CO    152.8° C.                               103                                                                              1  CH.sub.3CH.sub.2                                                                              N  CO    138.8° C.                               104                                                                              1  (C.sub.2 H.sub.5).sub.2N                                                                      N  CO    137.0° C.                               105                                                                              3  CH.sub.3CH.sub.2                                                                              N  CHOH  mp. 203.4° C./(R*, R*)                  106                                                                              3  CH.sub.3(CH.sub.2).sub.2                                                                      N  CHOH  mp. 194.5° C./(R*, R*)                                                 /H.sub.2 O                                     107                                                                              3  (C.sub.2 H.sub.5).sub.2N                                                                      N  CHOH  mp. 183.0° C./(R*, R*)                                                 /H.sub.2 O                                     108                                                                              5  (C.sub.7 H.sub.15).sub.2NCH.sub.2                                                             CH CHOH  (R*, R*)                                       109                                                                              5  (C.sub.12 H.sub.25).sub.2NCH.sub.2                                                            CH CHOH  (R*, R*)                                       __________________________________________________________________________

PHARMACOLOGICAL EXAMPLE

The anti-Helicobacter activity of the subject compounds was assessed bythe following in vitro test procedure.

EXAMPLE 6 Activity of test compounds versus Helicobacter

The activity of test compounds against Helicobacter pyIori wasdetermined against a standard set of 5 H. pylori strains obtained fromclinical material. Minimal inhibitory concentrations (MICs) weredetermined by measuring the activity of H. pylori urease after treatmentof growing cultures of the bacteria with the antimicrobial agents.

The test compounds were dissolved in DMSO at a concentration of 10⁻³ M.A dilution to 10⁻⁴ M in DMSO was also prepared. 10 μl volumes of thesesolutions were pipetted in the wells of Repli-Dishes (®Sterilin). Wellscontaining DMSO alone were included as controls in each Repli-Dish.Ampicillin((+)-6-[(2-amino-2-phenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid trihydrate) and metronidazole(2-methyl-5-nitro-1H-imidazol-1-ethanol) were included as referencecompounds in each batch of tests. (These compounds were tested at finalconcentrations of 10⁻⁵, 10⁻⁶, 10⁻⁷ and 10⁻⁸ M). Test plates were storedat 4° C. until used. The five isolates of H. pylori were maintained bysubculture on 10% blood agar every 2 or 3 days. The bacteria were grownat 37° C. under an atmosphere containing 5% oxygen, 10% CO₂ and 85%nitrogen. Suspensions of Helicobacter pylori for inoculum were preparedin Brain-heart infusion broth and adjusted to an absorbance of 1.5±0.3at 530 nM.

Freshly prepared 10% blood agar held at 45° C. was added in 1 ml volumesto the wells of the test plates, thus diluting the test compounds to10⁻⁵ and 10⁻⁶ M. The medium was allowed to cool, then 10 μl volumes ofbacterial suspension were pipetted on the agar surface. The plates wereincubated for 48 hours at 37° C. under the microaerophilic atmospheredescribed above. To facilitate reading of the plates and to ensure thatany growth on the media was truly H. pylori, advantage was taken of thehighly potent urea activity unique to this species. After the 48 hoursof incubation, 1 ml volumes of urease broth were gently added to eachRepli-Dish well and the plates were incubated at 37° C. for 2 hours. 100μl samples of fluid from each well were then pipetted into the wells of96-place microdilution plates. A purple colour was interpreted asgrowth, yellow-orange as no growth of H. pylori. By this means a clearend-point was obtained, from which the inhibitory effects could bedetermined. All compounds that showed activity at either of the twoconcentrations tested were retested with further dilutions included toestablish the MIC and with a broader spectrum of bacterial species astarget organisms. Thus far, the MIC values for compounds 1, 3, 7-9, 11,14, 17-20, 27, 28, 30, 33, 35-37, 40, 102, 105 and 106 were found to beequal or below 1 μM.

COMPOSITION EXAMPLES

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable acid additionsalt or a stereochemically isomeric form thereof.

EXAMPLE 7 Oral Drops

500 Grams of the A.I. was dissolved in 0.5 l of 2-hydroxypropanoic acidand 1.5 l of the polyethylene glycol at 60°˜80° C. After cooling to30°˜40° C. there were added 35 l of polyethylene glycol and the mixturewas stirred well. Then a solution of 1750 grams of sodium saccharin in2.5 l of purified water was added. Upon stirring were added 2.5 l ofcocoa flavor and polyethylene glycol q.s. to a volume of 50 l, providingan oral drop solution comprising 10 mg/ml of A.I. The resulting solutionwas filled into suitable containers.

EXAMPLE 8 Capsules

2- Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 gramsmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatincapsules, comprising each 20 mg of the active ingredient.

EXAMPLE 9 Film-Coated Tablets

Preparation of Tablet Core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in 200 mlof water. The wet powder mixture was sieved, dried and sieved again. 100Grams microcrystalline cellulose and 15 grams hydrogenated vegetable oilwere added. The whole was mixed well and compressed into tablets, giving10.000 tablets, each containing 10 mg of the active ingredient.

Coating

To a solution of 10 grams methyl cellulose in 75 ml of denaturatedethanol was added a solution of 5 grams of ethyl cellulose in 150 ml ofdichloromethane. Then there were added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol was molten anddissolved in 75 ml of dichloromethane. The latter solution was added tothe former and then there were added 2.5 grams of magnesiumoctadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentratedcolour suspension and the whole was homogenated. The tablet cores werecoated with the thus obtained mixture in a coating apparatus.

EXAMPLE 10 Suppositories

3 Grams A.I. was dissolved in a solution of 3 grams2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400.12 Gramssurfactant and triglycerides q.s. ad 300 grams were molten together. Thelatter mixture was mixed well with the former solution. The thusobtained mixture was poured into moulds at a temperature of 37°-38° C.to form 100 suppositories each containing 30 mg/ml of the A.I.

We claim:
 1. A compound having the formula ##STR29## a pharmaceuticallyacceptable addition salt or a stereochemically isomeric form thereof,whereinY is CH or N; R¹, R² and R³ each independently are hydrogen orC₁₋₄ alkyl; R⁴ and R⁵ each independently are hydrogen, halo, C₁₋₄ alkyl,C₁₋₄ alkyloxy, hydroxy, trifluoromethyl, trifluoromethyloxy ordifluoromethyloxy; R⁶ is hydrogen; or R⁶ is phenyl optionallysubstituted with halo; pyridinyl; furanyl; thienyl;3-chlorobenzo[b]thien-2-yl; trifluoromethyl; C₁₋₄ alkyloxycarbonyl;dihalophenylcyclopropanyl; C₃₋₆ cycloalkyl; adamantyl; C₂₋₆ alkenyloptionally substituted with halophenyl; or C₁₋₄ alkyl optionallysubstituted with halo, phenyl, halophenyl, dihalophenyl, phenyloxy,piperidinyl, pyrrolidinyl, piperazinyl, C₁₋₄ alkylpiperazinyl, C₁₋₄alkylcarbonylpiperazinyl, C₁₋₄ alkyloxycarbonylpiperazinyl, phthalimino,amino, mono- or di(C₁₋₂₀)alkylamino or C₃₋₆ cycloalkylamino; Z is C═O orCHOH; and ##STR30## is a radical of formula ##STR31##
 2. A compoundaccording to claim 1 wherein R⁶ is phenyl optionally substituted withhalo; pyridinyl; furanyl; thienyl; 3-chlorobenzo[b]thien-2-yl;trifluoromethyl; C₁₋₄ alkyloxycarbonyl; dihalophenylcyclopropanyl; C₃₋₆cycloalkyl; adamantyl; C₂₋₆ alkenyl optionally substituted withhalophenyl; or C₁₋₄ alkyl optionally substituted with halo, phenyl,halophenyl, dihalophenyl, phenyloxy, piperidinyl, pyrrolidinyl,piperazinyl, C₁₋₄ alkylpiperazinyl, C₁₋₄ alkylcarbonylpiperazinyl, C₁₋₄alkyloxycarbonylpiperazinyl, phthalimino, amino, mono- ordi(C₁₋₂₀)alkylamino or C₃₋₆ cycloalkylamino.
 3. A compound according toclaim 2 whereinR¹, R³ and R⁵ are hydrogen; R² is C₁₋₄ alkyl; R⁴ is halo;and Y is N.
 4. A compound according to claim 3 whereinR² is ethyl; R⁶ ispyridinyl, phenyl, halophenyl, benzyl, C₃₋₆ cycloalkyl, C₁₋₄alkyloxycarbonyl, methyl or trifluoromethyl; and ##STR32## is a radicalof formula (a-1) or (a-2).
 5. A compound according to claim 1 whereinsaid compoundis1-[4-[2-[1-(4-chlorobenzoyl)propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]-phenyl]-4-(cyclopropylcarbonyl)piperazine;1-(4-chlorobenzoyl)-4-[5-[2-[1-(4-chlorobenzoyl)propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]-2-pyridinyl]piperazine;1-benzoyl-4-[4-[2-[1-[(4-chlorophenyl)hydroxymethyl]propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]phenyl]piperazine;1-(4-chlorobenzoyl)-4-[4-[2-[1-[(4-chlorophenyl)hydroxymethyl]propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]phenyl]piperazine;apharmaceutically acceptable addition salt or a stereochemically isomericform thereof.
 6. A pharmaceutical composition comprising atherapeutically effective amount of a compound as claimed in any ofclaims 1 to 5 and a pharmaceutically acceptable carrier.
 7. A method fortreating Helicobacter infection in patients in need of the same, whichcomprises administering to said patients an effective amount of acompound of claim
 1. 8. A method for treating Helicobacter infection inpatients in need of the same, which comprises administering to saidpatients an effective amount of a compound of claim
 2. 9. A method fortreating Helicobacter infection in patients in need of the same, whichcomprises administering to said patients an effective amount of acompound of claim
 3. 10. A method for treating Helicobacter infection inpatients in need of the same, which comprises administering to saidpatients an effective amount of a compound of claim
 4. 11. A method fortreating Helicobacter infection in patients in need of the same, whichcomprises administering to said patients an effective amount of acompound of claim 5.